The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies is studied with emphasis on the role of pharmacologic monitoring and on both pre-clinical and clinical pharmacologic studies of Phase I agents. Preclinical, Phase I and pharmacokinetic studies of a variety of new agents including All-trans retinoic acid, Topotecan, Pyrazoloacridine, Taxotere, Taxol, Piroxantrone, Cyclopentenylcytosine (CPE-C) and Amifostine are in progress. In addition, Phase I, Phase II and correlative pharmacologic studies evaluating new approaches or new formulations of older chemotherapeutic agents including thiotepa, intravenous 6-thioguanine and PEG-L-asparaginase are being pursued. Phase II studies of agents previously studied both preclinically and in Phase I trials in this section are also in progress (e.g.Fazarabine, ICRF-187). Several collaborative studies in which this section provides pharmacologic support for important clinical studies in other COP Branches are being pursued. A major effort of this project is to investigate experimental approaches to the treatment of CNS malignancy. A unique primate model is utilized to study the CNS pharmacokinetics of various intrathecally and intravenously administered chemotherapeutic agents; to evaluate the neurotoxicities of various CNS treatments; and to evaluate and screen newer CNS treatment modalities and drug schedules. Information gained from the studies with this model is then applied to the design of clinical treatment protocols. Clinical studies of intrathecal AZQ, intrathecal 6-MP, and intrathecal mafosfamide, all novel approaches developed in this model, are in progress. A clinical study evaluating continuous intra-CSF drug infusion via a unique indwelling drug delivery device also is under way. Two new trials evaluating the role of systemically and intrathecally administered Carboxypeptidase-G2 have begun. As part of the Pediatric Branch AIDS research effort, the PETS Section is studying the clinical pharmacology of antiretroviral agents in children. This effort is a natural extension of our work on the clinical pharmacology of anticancer drugs, since most of the antiretroviral agents are nucleoside analogs, similar to the antimetabolites used in the treatment of pediatric cancers. The CNS pharmacology of antiretroviral therapies is being systematically evaluated in our non-human primate model, to determine which agents may be most effective against CNS HIV infection. We also participate in the design of clinical trials of antiretroviral agents in children and perform detailed pharmacokinetic studies in the patients treated on these trials.